The structure and microarchitecture of secondary lymphoid organs (SLO) plays a fundamental role in the initiation and maintenance of immune responses. Cells that are important to structure and microarchitecture are often targets of viral infection and disruption of SLO structure occurs in many viruses (including HIV), yet little is known about how lymphoid disruption occurs during viral infection and how this affects immune responses and viral clearance. The goal of this application is to unravel the mechanisms involved in SLO disorganization during viral infection and to directly assess the impact on the coordination and kinetics of lymphocyte activation and viral clearance with the hypothesis that deregulation of immune cell interactions impedes immunity to chronic infections and contributes to immune suppression during chronic infections. Using a well-established system of persistent non-lytic viral infection to model changes in SLO architecture during chronic infection coupled with a key discovery in this model that type I interferon signaling is important in disruption of splenic architecture, I will use molecular and cellular approaches to (1) dissect the mechanism by which SLO disruption occurs, (2) examine how abnormal SLO morphology interrupts cell-cell interactions, and (3) whether manipulation of architecture can influence immune responses and viral outcome. In addition to expanding our knowledge of control and regulation of adaptive immunity, this research will inform the development of therapeutic strategies during viral infection.